Orphanet Journal of Rare Diseases | Impact of Cardiac and Renal Involvement Patterns on Arrhythmias and Cardiovascular Outcomes in Fabry Disease Patients

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This study pioneers the classification of Fabry disease patients based on cardiac and renal involvement patterns, systematically evaluating arrhythmia burden and prognostic significance across different phenotypic subgroups. Results demonstrate that LVMWT is an independent predictor of cardiovascular events, highlighting the importance of comprehensive risk stratification and multidisciplinary management strategies for Fabry disease.

 

Literature Overview
This article, \"Arrhythmias and clinical outcomes in Fabry disease with cardiac and renal involvement\" published in Orphanet Journal of Rare Diseases, reviews and summarizes the impact of cardiac and renal involvement patterns on cardiovascular risk stratification in Fabry disease (FD). The study enrolled 83 FD patients, stratified into four groups based on cardiac and renal involvement: non-affected (24.1%), cardiac-only (24.1%), renal-only (18.1%), and co-affected (33.7%). With a median follow-up of 39 months, it assesses arrhythmia burden and major cardiovascular outcomes.

Background Knowledge
Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A (α-GalA) deficiency, leading to Gb3 (GL-3) deposition in multiple organs including heart, kidneys, and nervous system. The disease exhibits heterogeneity among patients, presenting with organ-specific involvement patterns. However, no current cardiovascular risk stratification system exists based on organ involvement patterns. While existing studies focus on independent mechanisms of cardiomyopathy and nephropathy in FD, the arrhythmia manifestations across different phenotypes and their impact on cardiovascular outcomes remain unclear. This study provides novel stratification strategies for clinical practice through retrospective cohort analysis evaluating arrhythmia burden and cardiovascular event occurrences in different FD phenotypes.

 

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Research Methods and Experiments
The study employed a single-center retrospective cohort design, enrolling 83 FD patients diagnosed at the First Affiliated Hospital of Zhejiang University School of Medicine between January 2020 and December 2024. Patients were categorized into four groups based on cardiac and renal involvement: non-affected (n=20), cardiac-only (n=20), renal-only (n=15), and co-affected (n=28). Baseline ECG and echocardiography data were collected, supplemented with CMR, 24-hour urine protein, and renal biopsy information. Primary endpoints included cardiovascular mortality, new-onset severe heart failure, atrial fibrillation occurrence, and clinically significant arrhythmias requiring device implantation. Prognostic correlations were evaluated using Kaplan-Meier analysis and Cox regression models.

Key Findings and Perspectives

• Arrhythmia burden in FD patients is substantial, with significant differences between phenotypes, particularly the highest arrhythmia incidence in combined cardiac and renal involvement groups.
• LVMWT (left ventricular maximum wall thickness) showed significant association with cardiovascular events as a continuous variable, maintaining statistical significance in multivariate analysis independent of other factors.
• eGFR (estimated glomerular filtration rate) demonstrated prognostic relevance in univariate analysis but lost significance in multivariate models, potentially due to sample size limitations.
• FD patients with combined cardiac and renal involvement exhibited the worst prognosis with earliest and most rapid event occurrence, emphasizing the need for intensified multi-system management.
• ECG parameters such as QRS duration and QTc interval were prolonged in cardiac-only and co-affected groups, suggesting FD patients should avoid QT-prolonging medications.

Research Implications and Future Directions
This study represents the first systematic classification of FD patients based on cardiac and renal phenotypes, providing novel insights into arrhythmia burden and cardiovascular risk stratification. Findings establish a new framework for clinical risk stratification, emphasizing LVMWT as an independent predictive marker. Future studies should expand sample sizes and implement multi-center prospective designs to validate the generalizability of this stratification system, while deeper genotype-phenotype correlation analyses could optimize therapeutic strategies.

 

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Conclusion
Fabry disease (FD) is a rare X-linked recessive genetic disorder characterized by cardiomyopathy and nephropathy. Through systematic review of clinical data from FD patients, this study reveals significant impacts of different cardiac and renal involvement patterns on arrhythmia burden and cardiovascular prognosis. Notably, patients with cardiac involvement (cardiac-only and co-affected groups) exhibit significantly increased major cardiovascular event rates, with LVMWT serving as an independent predictor. While renal function indicators like eGFR correlate with outcomes in univariate analysis, they lose significance in multivariate models, likely due to sample size constraints. These findings provide a novel risk stratification framework for FD patients, underscoring the clinical necessity for comprehensive management of multi-system involvement. Future large-scale prospective studies will help validate this stratification system and support individualized treatment strategies.

 

Xiang Yin, Zhuonan Song, Xiangjie Sun, Hui Yan, and Xiaosheng Hu. Arrhythmias and clinical outcomes in Fabry disease with cardiac and renal involvement. Orphanet Journal of Rare Diseases.